Person:
Juárez Martín-Delgado, Ignacio

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First Name
Ignacio
Last Name
Juárez Martín-Delgado
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Medicina
Department
Inmunología, Oftalmología y ORL
Area
Inmunología
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Now showing 1 - 10 of 12
  • Publication
    Major histocompatibility complex complement (MHC) Bf alleles show trans species evolution between man and chimpanzee
    (Nature, 2023-10-04) Arnaiz Villena, Antonio; Juárez Martín-Delgado, Ignacio; Martín Villa, José Manuel; Ignacio Juarez; Alejandro Sánchez-Orta; José Manuel Martín-Villa; Fabio Suarez-Trujillo
    AbstractHLA and disease studies by using single allele statistics have been fruitless during the last 40 years for explaining association pathogenesis of the associated diseases.Other approaches are necessary to untangle this puzzle. We aim to revisit complement alleleism in humans and primates for both studying MHC and disease association to complotypes and extended MHC haplotypes in order to also explain the positive directional selection of maintaining immune response genes (complement, MHC adaptive and MHC non-specific genes) that keeps these three type of genes together in a short chromosome stretch (MHC) for million years. These genes may be linked to conjointly avoid microbes attack and autoimmunity. In the present paper, it is obtained a new Bf chimpanzee allele, provisionaly named Patr-Bf*A:01,that differs from other Bf alleles by having CTG at eleventh codon of exon 2 in order to start the newly suggested methodology and explain functional and evolutionary MHC obscure aspects. Exons 1 to 6 of Ba fragment of Bf gene were obtained from chimpanzee. This new chimpanzee Factor B allele (Patr-Bf*A:01) is to be identical to a infrequent human Bf allele (SNP rs641153); it stresses the strong evolutive pressure upon certain alleles that are trans specific. It also may apply to MHC extended haplotipes which may conjointly act to start an adequate immune response. It is the first time that a complement MHC class III allele is described to undergo trans species evolution,in contrast to class I and class II alleles which had already been reported . Allelism of complement factors are again proposed for studying MHC complement genes, complotypes, and extended MHC haplotypes which may be more informative that single MHC marker studies.
  • Publication
    HLA study in Mexico Nahua/Aztec Amerindians: Close relatedness to the ancient Central America ethnic groups
    (Elsevier, 2023-05) Suarez Trujillo, Fabio; Vargas Alarcon, Gilberto; Juárez Martín-Delgado, Ignacio; Gil Martin, Roberto; Granados, Julio; Vaquero Yuste, Christian; Martín Villa, José Manuel; Arnaiz Villena, Antonio
    Nahua population (also named Aztec or Mexica) was studied for HLA class II genes in a Mexican rural city (Santo Domingo Ocotitlan, Morelos State) belonging to the nowadays Náhuatl speaking areas in Mexico. The most frequent HLA class II alleles were typical Amerindian (HLA-DRB1*04:07, DQB1*03:01 DRB1*04:03 or DRB1*04:04) and also were some calculated extended haplotypes (HLA-DRB1*04:07-DQB1*03:02,DRB1*08:02-DQB1*04:02, or DRB1*10:01-DQB1*05:01 among others). When using HLA-DRB1 Neís genetic distances, our isolated Nahua population was found to be close to other Central America Amerindians like the ancient-established Mayans or Mixe. This may suggest that Nahuas origin was also from Central America. It contrasts to legend that assumes they came from the North, and they built the Aztec Empire after submitting Central America neighbouring ethnic groups before 1519 CE when Spaniards led by Hernán Cortés arrived to Mexico
  • Publication
    Evolution and molecular interactions of major histocompatibility complex (MHC)-G, -E and -F genes
    (Springer Link, 2022-08) Suarez-Trujillo, Fabio; Juarez, Ignacio; Rodríguez-Sainz, Carmen; Palacio-Gruber, José; Vaquero-Yuste, Christian; Molina-Alejandre, Marta; Fernández-Cruz, Eduardo; Martin-Villa, José Manuel; Arnaiz Villena, Antonio; Juárez Martín-Delgado, Ignacio; Fernández-Cruz Pérez, Eduardo; Martín Villa, José Manuel
    AbstractClassicalHLA(Human Leukocyte Antigen) is the Major Histocompatibility Complex (MHC) in man. HLA genes and disease association has been studied at least since 1967 and no firm pathogenic mechanisms have been established yet.HLA-Gimmune modulation gene (and also-Eand-F) are starting the same arduous way: statistics and allele association are the trending subjects with the same few results obtained byHLAclassical genes, i.e., no pathogenesis may be discovered after many years of a great amount of researchers’ effort. Thus, we believe that it is necessary to follow different research methodologies: (1) to approach this problem, based on how evolution has worked maintaining together a cluster of immune-related genes (the MHC) in a relatively short chromosome area since amniotes to human at least, i.e., immune regulatory genes (MHC-G, -E and -F), adaptive immune classical class I and II genes, non-adaptive immune genes like (C2, C4 and Bf) (2); in addition to using new in vitro models which explain pathogenetics ofHLAand disease associations. In fact, this evolution may be quite reliably studied during about 40 million years by analyzing the evolution ofMHC-G, -E, -F, and their receptors (KIR—killer-cell immunoglobulin-like receptor, NKG2—natural killer group 2-, or TCR-T-cell receptor—among others) in the primate evolutionary lineage, where orthology of these molecules is apparently established, although cladistic studies show thatMHC-GandMHC-Bgenes are the ancestral class I genes, and that New World apesMHC-Gis paralogous and not orthologous to all other apes and manMHC-Ggenes. In the present review, we outline past and possible future research topics: co-evolution of adaptiveMHCclassical (class I and II), non-adaptive (i.e., complement) and modulation (i.e., non-classical class I) immune genes may imply that the study of full or part of MHC haplotypes involving several loci/alleles instead of single alleles is important for uncovering HLA and disease pathogenesis. It would mainly apply to starting research on HLA-G extended haplotypes and disease association and not only using single HLA-G genetic markers.
  • Publication
    HLA in North Colombia Chimila Amerindians
    (Elsevier, 2018-04-13) Arnaiz Villena, Antonio; Palacio Grüber, Jose; Juárez Martín-Delgado, Ignacio; Hernández, Ennio; Muñiz, Ester; Bayona, Brayan; Campos, Cristina; Nieto, Jorge; Martín Villa, José Manuel; Silvera, Carlos
    HLA-A,-B,-C,-DRB1 and -DQB1 alleles have been studied in Chimila Amerindians from Sabana de San Angel (North Colombian Coast) by using high resolution molecular typing. A frequent extended haplotype was found:HLA-A*24:02-B*51:10-C*15:02-BRB1*04:07-DQB1*03:02 (28.7%) which has also been described in Amerinndian Mayos Mexican population (Mexico, California Gulf, Pacific Ocean). Other haplotypes had already been found in Amerindians from Mexico (Pacific and Atlantic Coast), Peru (highlands and Amazon Basin), Bolivia and North USA. A geographic pattern according to HLA allele or haplotype frequencies is lacking in Amerindians, as already known. Also, five new extended haplotypes were found in Chimila Amerindians. Their HLA-A*24:02 high frequencies characteristic is shared with aboriginal populations of Taiwan; also, HLA-C*01:02 high frequencies are found in New Zealand Maoris, New Caledonians and Kimberly Aborigines from Australia. Finally, this study may show a model of evolutionary factors acting and rising one HLA allele frequency (-A*24:02), but not in others that belong to the same or different HLA loci.
  • Publication
    A Reliable and Standardizable Differential PCR and qPCR Methodology Assesses HER2 Gene Amplification in Gastric Cancer
    (MDPI, 2021-06-10) Juárez Martín-Delgado, Ignacio; Toro Fernandez, Juan Francisco; Vaquero Yuste, Christian; Molina Alejandre, Marta; Lasa, Inmaculada; Gomez, Remedios; Lopez, Adela; Martín Villa, José Manuel; Gutierrez, Alberto
    We have applied two PCR techniques, differential PCR (diffPCR) and qPCR for the identification of HER2 gene amplifications in genomic DNA of tumor and distal gastric samples from patients with gastric cancer. The diffPCR technique consists of the simultaneous amplification of the HER2 gene and a housekeeping gene by conventional PCR and the densitometric analysis of the bands obtained. We established a cut-off point based on the mean and standard deviation analyzing the DNA of 30 gastric tissues from patients undergoing non-cancer gastrectomy. diffPCR and qPCR yielded consistent results. HER2-overexpression was detected in 25% of patients and was further confirmed by immunohistochemistry and immunofluorescence. The approaches herein described may serve as complementary and reliable methods to assess HER2 amplification.
  • Publication
    HLA-G: Too Much or Too Little? Role in Cancer and Autoimmune Disease
    (Frontiers, 2022-01-27) Martín Villa, José Manuel; Juárez Martín-Delgado, Ignacio; Fernández-Cruz Pérez, Eduardo; Arnaiz Villena, Antonio; Christian Vaquero-Yuste; Marta Molina-Alejandre; Fabio Suárez-Trujillo; Adrián López-Nares; José Palacio‐Gruber; Luis Barrera-Gutiérrez; Carmen Rodríguez-Sainz
    HLA-G is a non-classical HLA class I molecule with immunomodulatory properties. It was initially described at the maternal-fetal interface, and it was later found that this molecule was constitutively expressed on certain immuneprivileged tissues, such as cornea, endothelial and erythroid precursors, and thymus. The immunosuppressive effect of HLA-G is exerted through the interaction with its cognate receptors, expressed on immunocompetent cells, like ILT2, expressed on NK, B, T cells and APCs; ILT4, on APCs; KIR, found on the surface of NK cells; and finally, the co-receptor CD8. Because of these immunomodulatory functions, HLA-G has been involved in several processes, amongst which organ transplantation, viral infections, cancer progression, and autoimmunity. HLA-G neo-expression on tumors has been recently described in several types of malignancies. In fact, tumor progression is tightly linked to the presence of the molecule, as it exerts its tolerogenic function, inhibiting the cells of the immune system and favoring tumor escape. Several polymorphisms in the 3’UTR region condition changes in HLA-G expression (14bp and +3142C/G, among others), which have been associated with both the development and outcome of patients with different tumor types. Also, in recent years, several studies have shown that HLA-G plays an important role in the control of autoimmune diseases. The ability of HLA-G to limit the progression of these diseases has been confirmed and, in fact, levels of the molecule and several of its polymorphisms have been associated with increased susceptibility to the development of autoimmune diseases, as well as increased disease severity. Thus, modulating HLA-G expression in target tissues of oncology patients or patients with autoimmune diseases may be potential therapeutic approaches to treat these pathological conditions.
  • Publication
    Higher prevalence of LAP+ (Latency TGFβ-Associated Peptide) T cells at the tissue level in patients with early gastric cancer
    (Elsevier, 2022-12) Aguinaga Barrilero, Ana; Juárez Martín-Delgado, Ignacio; Vaquero Yuste, Christian; Molina Alejandre, Marta; Gutiérrez Calvo, Alberto; Lasa, Inmaculada; López, Adela; Gómez, Remedios; Molanes López, Elisa María; Martín Villa, José Manuel
    The presence of cells with regulatory functions in patients with cancer is one of the mechanisms whereby the immune system cannot confront tumor growth. We sought to determine the prevalence of immunoregulatory T-cell subpopulations, expressing the latency TGFβ-associated peptide (LAP), in patients with gastric adenocarcinoma. T cells were enriched from blood or gastric tissue (tumoral, TT or tumor-free, TF) samples from 22 patients, 6 with early (EGC) and 16 with advanced gastric cancer (AGC). CD4, CD8, LAP, FoxP3 and IFN-γ were measured by cytometry. CD8 + LAP + cells were increased at tumoral sites, especially in early stages of the disease, as compared to tumor-free explants (EGC 5.28 % [4.67-6.64]*; AGC 2.90 % [1.37-4.44]; TF 3.14 % [2.33-4.16]; *p < 0.05 vs TF). Likewise, the LAP+/CD8 + LAP- ratio is increased in gastric samples from patients with early disease (EGC 0.38 [0.30-0.45]*, AGC 0.12 [0.07-0.14]; TF 0.12 [0.09-0.31]; *p < 0.05 vs AGC).Disease progression is accompanied by decreased LAP membrane expression and, probably, increased LAP secretion, therefore limiting the response to the tumor.
  • Publication
    An Experimental DUAL Model of Advanced Liver Damage
    (Lippincott, Williams & Wilkins, 2021-06) Benede Ubieto, Raquel; Estévez Vázquez, Olga; Guo, Feifei; Chen, Chaobo; Gómez Del Moral Martín-Consuegra, Manuel María; Lamas Paz, Aranzazu; Morán, Laura; López Alcántara, Nuria; S. Mazariegos, Marina; Zheng, Kang; Juárez Martín-Delgado, Ignacio; Martín Villa, José Manuel; Asensio, Iris; Vaquero Martín, Francisco Javier; Peligros Gómez, María Isabel; Romero Gómez, Manuel; Bañares Cañizares, Rafael; Cubero Palero, Francisco Javier; Nevzorova, Yulia
    Individuals exhibiting an intermediate alcohol drinking pattern in conjunction with signs of metabolic risk present clinical features of both alcohol-associated and metabolic-associated fatty liver diseases. However, such combination remains an unexplored area of great interest, given the increasing number of patients affected. In the present study, we aimed to develop a preclinical DUAL (alcohol-associated liver disease plus metabolic-associated fatty liver disease) model in mice. C57BL/6 mice received 10% vol/vol alcohol in sweetened drinking water in combination with a Western diet for 10, 23, and 52 weeks (DUAL model). Animals fed with DUAL diet elicited a significant increase in body mass index accompanied by a pronounced hypertrophy of adipocytes, hypercholesterolemia, and hyperglycemia. Significant liver damage was characterized by elevated plasma alanine aminotransferase and lactate dehydrogenase levels, extensive hepatomegaly, hepatocyte enlargement, ballooning, steatosis, hepatic cell death, and compensatory proliferation. Notably, DUAL animals developed lobular inflammation and advanced hepatic fibrosis. Sequentially, bridging cirrhotic changes were frequently observed after 12 months. Bulk RNA-sequencing analysis indicated that dysregulated molecular pathways in DUAL mice were similar to those of patients with steatohepatitis. Conclusion: Our DUAL model is characterized by obesity, glucose intolerance, liver damage, prominent steatohepatitis and fibrosis, as well as inflammation and fibrosis in white adipose tissue. Altogether, the DUAL model mimics all histological, metabolic, and transcriptomic gene signatures of human advanced steatohepatitis, and therefore serves as a preclinical tool for the development of therapeutic targets.
  • Publication
    TGFB1 polymorphisms and TGF‐β1 plasma levels identify gastric adenocarcinoma patients with lower survival rate and disseminated disease
    (Wiley, 2020-12-04) Alberto Gutierrez; Christian Vaquero‐Yuste; Adela López; Inmaculada Lasa; Remedios Gómez; Juárez Martín-Delgado, Ignacio; Molanes López, Elisa María; Martín Villa, José Manuel
    AbstractTGF‐β1 is involved in tumour growth. Four TGFB1 SNPs and TGF‐β1 production by stimulated PBMC were determined in seventy‐eight gastric adenocarcinoma patients. In addition, TGF‐β1 levels were measured in the plasma of further thirty patients. rs1800471‐G/C genotype was prevalent in patients (20.7%) compared to controls (8.4%), as it also was the rs1800468 SNP‐G/A genotype in stage IV patients (20.7%) compared to stage I, II and III patients, combined (10.3%). Conversely, the T/T rs1800469 SNP‐T/T genotype was absent in the former group and present in 19.0% in the latter. Furthermore, the rs1800469‐C/rs1800470‐T (CT) haplotype was found in 15.0% of stage IV patients as compared to 3.0% of the remaining patients (3.0%) and also identifies patients with worse five‐year life expectancy (P = .03). TGF‐β1 synthesis by stimulated PBMCs was significantly lower in patients with the risk SNPs or haplotype, compared to the alternative genotype. Finally, TGF‐β1 plasma levels were lower in patients with worse life expectancy. Analysis of TGFB1 SNPs and measurement of plasma TGF‐β1 levels serves to identify patients at risk of developing a more aggressive disease.
  • Publication
    HLA-G 3’UTR Polymorphisms Are Linked to Susceptibility and Survival in Spanish Gastric Adenocarcinoma Patients
    (Frontiers Media, 2021-09-07) Vaquero Yuste, Christian; Juárez Martín-Delgado, Ignacio; Molina Alejandre, Marta; Molanes López, Elisa María; López Nares, Adrián; Suárez Trujillo, Fabio; Gutiérrez Calvo, Alberto; Fernández-Cruz Pérez, Eduardo; Rodríguez Sainz, Carmen; Martín Villa, José Manuel; Arnaiz Villena, Antonio
    HLA-G is a non-classical class I HLA molecule that induces tolerance by acting on receptors of both innate and adaptive immune cells. When overexpressed in tumors, limits surveillance by the immune system. The HLA-G gene shows several polymorphisms involved in mRNA and protein levels. We decided to study the implication of two polymorphisms (rs371194629; 14bp INS/DEL and rs1063320; +3142 C/G) in paired tissue samples (tumoral and non-tumoral) from 107 Spanish patients with gastric adenocarcinoma and 58 healthy control individuals, to assess the possible association of the HLA-G gene with gastric adenocarcinoma susceptibility, disease progression and survival. The presence of somatic mutations involving these polymorphisms was also analyzed. The frequency of the 14bp DEL allele was increased in patients (70.0%) compared to controls (57.0%, p=0.025). In addition, the haplotype formed by the combination of the 14bp DEL/+3142 C variants is also increased in patients (54.1% vs 44.4%, p=0.034, OR=1.74 CI95% 1.05-2.89). Kaplan-Meier analysis revealed that 14bp DEL/DEL patients showed lower 5-year life-expectancy than INS/DEL or INS/INS (p=0.041). Adjusting for TNM staging (Cox regression analysis) disclosed a significant difference in death risk (p=0.03) with an expected hazard 2.6 times higher. Finally, no somatic mutations were found when comparing these polymorphisms in tumoral vs non-tumoral tissues, which indicates that this is a preexisting condition in patients and not a de novo, tumor-restricted, event. In conclusion, the variants predominant in patients were those increasing HLA-G mRNA stability and HLA-G expression, clearly involving this molecule in gastric adenocarcinoma susceptibility, disease progression and survival and making it a potential target for immunotherapeutic approaches.